GLYCOGEN SYNTHASE KINASE-3 (GSK3) ACTIVITY PLAYS CRUCIAL ROLE IN HUMAN PANCREATIC CANCER CELL PROLIFERATION AND SURVIVAL

Abstract

Background: GSK3 is a serine/threonine kinase that was first identified for its role in glycogen metabolism. Beyond that, we now know that it also plays an important role in other cellular processes such as cell proliferation, survival and transformation. However, cellular context greatly influence its contribution to these different cellular processes. Aim: To evaluate the contribution of the GSK3 activity in proliferation and survival of human pancreatic cancer cells. Methods: Different cell lines were used (PANC-1, MIA PaCa-2, BxPC-3) and treated with specific GSK3 inhibitors (SB216763, AR-A014418). Results: 1- During G1-S phase progression, low GSK3 activity was initially observed, but GSK3 was reactivated in mid-G1 up to the S phase of the cell cycle. 2- Inhibition of GSK3 activity from mid-G1 to the S phase (when GSK3 is typically reactivated) was sufficient to block pRb hyperphosphorylation. 3- Moreover, prolonged inhibition of GSK3 (48/72 h) induced PARP cleavage and caspase-7 activation. 4- This apoptotic response was associated with increased Bim and reduced Bcl-2 protein levels. 5- A 48 h recovery period (in normal cultured medium) following a 24 h SB216763 treatment was unable to protect the cells against apoptosis. Conclusion: Taking together, these results suggest that GSK3 participates in human pancreatic cancer cell proliferation, especially in late G1-S phase progression of the cell cycle. In addition, GSK3 activity plays a crucial role in cell survival as inhibition of GSK3 activity for 24 h is sufficient to induce irreversible cell death.